A long-term goal of our research for the past 20 years has been to understand mechanisms through which the immune system modulates function and dysfunction of skeletal muscle. In the project for which we request support, we will examine the function of a specific population of immune cells that have the potential to influence sarcopenia, the loss of muscle mass during aging. Currently, there are no treatments for sarcopenia in humans other than exercise and dietary interventions that may not be applicable for the aged. Validation of our model for immune-cell modulation of sarcopenia could provide a gateway to new therapeutic strategies for the slowing of sarcopenia. This outcome would have substantial significance for treating major health problems in the aging human population in which degradation of lifestyle, loss of independent function and development of inactivity-associated diseases can arise from the loss of muscle mass and physical activity in the elderly population. We hypothesize that aging of the immune system contributes to sarcopenia through two processes: 1) reductions in the capacity of bone marrow derived myelomonocytic cells to fuse with skeletal muscle, and 2) shifts in macrophages to a phenotype that promotes muscle wasting. Our experiments that are designed to test this hypothesis will address the following aims: Aim 1: Determine the fate of select immune cell populations in aging muscle. Aim 2: Determine whether diminishing selected immune cell populations affects sarcopenia or the regenerative capacity of muscle during aging. Aim 3: Test whether manipulation of the development of specific immune cell populations can influence sarcopenia. The findings of this investigation will provide the first information concerning the fate of cells of the myelomonocytic lineage in aging muscle and provide new insights into the mechanisms through which cells of that lineage can affect the regenerative capacity of aging muscle. That information can provide the foundation for new therapeutic strategies for addressing sarcopenia, a major health problem in the elderly. PUBLIC HEALTH RELEVANCE: Sarcopenia is the progressive loss of muscle mass that occurs in the elderly that greatly reduces their quality of life and susceptibility to injury. We propose to test whether aging of the immune system reduces the regenerative capacity of aging muscle. Validation of our model for immune-cell modulation of sarcopenia could provide a gateway to new therapeutic strategies for the slowing of sarcopenia.